This invention relates to treatments for Type II diabetes.
Diabetes mellitus is characterized by hyperglycemia, the delayed onset of a highly specific set of microvascular abnormalities in the retina, kidney, and peripheral nerves, and an unusually high prevalence of atherosclerotic vascular disease, qualitatively similar to that seen in the nondiabetic population. The illness is common, affecting at least 2% of individuals of all ages in the U.S. Two broad clinical forms, i.e., Type I and Type II, encompass &gt;98% of all cases.
Type I diabetes, previously called juvenile-onset or early-onset diabetes, accounts for 10-20% of all cases. The underlying cause of Type I diabetes appears to be an autoimmune destruction of the insulin-secreting .beta.-cells of the pancreas.
The proximate cause of Type II diabetes, which accounts for 80-90% of all cases, is not yet known. It is known, however, that this illness is found in 1 out of 20 adults over the age of 40 and that it increases in prevalence with age. It is also known that the disease is characterized by two coexisting metabolic defects. First, nearly all patients with Type II diabetes exhibit a marked resistance to the hypoglycemic actions of insulin. In physiologic terms, uptake of glucose into skeletal muscle (i.e., the major site of insulin-mediated glucose conversion) is impaired at all plasma insulin concentrations; this is combined with a failure of low concentrations of insulin to suppress glucose production by the liver (see, e.g., DeFronzo, Diabetes 37:667, 1988). Such insulin resistance results in a situation where the patient, although producing detectable and often considerable amounts of endogenous insulin, is unable to overcome the impedence to insulin action. In certain instances, insulin resistance is further complicated by a coexisting deficiency in endogenous insulin secretion.
Such chronic hyperglycemia with or without insulin deficiency often results in unfavorable secondary consequences. For example, insulin action and insulin secretion may be further impaired by processes different, and additive to, those which initiated the insulin resistance and deficiency (Unger and Grunby, Diabetologia 28:119, 1985). In addition, chronic hyperglycemia is thought to cause renal, retinal, and neuropathic complications and to contribute substantially to accelerated atherosclerosis.